Rett syndrome (RTT) is a complex developmental disorder primarily arising from mutations in MECP2 and occurring almost entirely in girls. Despite strong perinatal expression of Mecp2, RTT symptoms usually appear later around the first year of life, leading to developmental regression. Symptoms can include stereotypic dyskinesias, autistic features, including language delay and regression, breathing abnormalities, and abnormal central EEG spikes. While Rett syndrome is relatively rare (~1:15:000), polymorphisisms of MECP2 and changes in expression levels have been associated with autism and schizophrenia. Often grouped with autism, whether RTT syndrome is analogous to other autism spectrum disorders (ASD) is controversial. Currently there are no established models for studying cortical processing abnormalities in RTT or ASD. Preliminary data from our lab using a mouse strain modeling a null-mutation reproduce auditory processing abnormalities nearly identical to those described in autistic individuals, including a true endophenotype of increased induced- gamma. Concurrent work from our laboratory demonstrates changes of excitability in these mice pointing to abnormalities in local circuit inhibition. This is consistent with prevalent theories of increased cortical excitability in ASD. We propose to extend this work combining in vitro and in vivo physiological approaches to understand the cortical changes associated with the auditory event-related potentials abnormalities common to the RTT mouse model and individuals with ASD. The goals of this proposal are, determine how disruption in Mecp2 effects local circuit function and auditory processing in RTT, and to understand cortical abnormalities that may cause the ASD-related sensory processing differences generated by the RTT mouse model. PUBLIC HEALTH RELEVANCE: We have found a striking similarity between auditory responses reported in autistic individuals and a mouse model of Rett syndrome (RTT). Using both in vivo and in vitro approaches, this proposal takes advantage these similarities to identify and understand underlying cortical mechanisms disrupted in RTT and autism. Leading from positive preliminary data, it further tests the efficacy of antidepressants to reverse these differences.